In conformity with the general scientific goals of this grant (now in the -20 year), the overall objective for the next 5-year project period is to study six forms of nephrogenic diabetes insipidus, four hereditary (in mice) and two acquired (lithium-induced and potassium-deficiency, in mice or rats). The aim in each instance will be to identify the cause(s) of the defect, to see if the deficiencies can be corrected by various medicinal interventions, and hence possibly to point the way for more effective treatment 14 analogous disorders in human patients. The mouse models to be tested include: VII+/+ (normal, control); VII Os/+ (chronic renal failure); DI +/+ Severe (analogue of human nephrogenic DI); DI +/+ Non-severe (mild concentrating defect); DI Os/+ (combination of VII Os/+ and DI +/+ Non-severe, but excreting hypotonic urine); VII +/+ given LiCl (analogue of the human disorder); and VII +/+ in potassium-deficiency (analogue of the human disorder). The questions to be asked include: (a) Is there deficient vasopressin-mediated water permeability of late distal tubules and collecting ducts? When deficient buildup of the corticopapillary interstitial osmotic gradient is present, (b) Is it due to an inherent deficiency of NaCl transport in medullary thick ascenting limbs of Henle (mTALH)? (c) Is it due to osmotic diuresis per nephron? Or (d) Is it secondary to water diuresis? The methods to be applied to answer these questions include: For question (a), (1) Freeze-fracture electron microscopy, to measure intramembraneous particles in apical membranes of collecting ducts; (2) Isolated, perfused collecting ducts in vitro, to measure osmotic water permeability; and (3) Comparison of papillary interstitial vs. urinary osmolalities. For question (b), (4) Isolated, perfuse mTALH in vitro, to measure transepithelial voltage and Cl flux. For questions (c), (5) Mannitol diuresis combined with (1) and (2). Question (d) will be answered by exclusion, i.e., by eliminating possibilities (b) and (c). Correction of any defects, if found, will be attempted by exposure to AVP, DDAVP, forskolin, MIX, and chlorphenylthio cyclic AMP, singly or together, in vitro and in vivo. Plasma and urinary vasopressin (by RIA), serum creatinine (and plasma Na, Cl, K, and Li when appropriate) will be measured for each animal model.